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Review
. 2022 Jul 13;43(4):743-760.
doi: 10.1210/endrev/bnab042.

From Molecule to Behavior: Hypocretin/orexin Revisited From a Sex-dependent Perspective

Xiao-Bing Gao  1 , Tamas L Horvath  1
Affiliations
Review

From Molecule to Behavior: Hypocretin/orexin Revisited From a Sex-dependent Perspective

Xiao-Bing Gao et al. Endocr Rev. .

Abstract

The hypocretin/orexin (Hcrt/Orx) system in the perifornical lateral hypothalamus has been recognized as a critical node in a complex network of neuronal systems controlling both physiology and behavior in vertebrates. Our understanding of the Hcrt/Orx system and its array of functions and actions has grown exponentially in merely 2 decades. This review will examine the latest progress in discerning the roles played by the Hcrt/Orx system in regulating homeostatic functions and in executing instinctive and learned behaviors. Furthermore, the gaps that currently exist in our knowledge of sex-related differences in this field of study are discussed.

Keywords: homeostasis; hypocretin/orexin; lateral hypothalamic area (LHA); motivational behavior; sex-related difference; social behavior.

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Figures

Graphical Abstract
Graphical Abstract
Figure 1.
Figure 1.
A diagram depicting major functions of the Hcrt/Orx system in animals. Brain circuits regulating physiological homeostasis and controlling complex behavior converge onto the Hcrt/Orx system, which becomes an essential hub in the brain to mediate the interplay between physiological homeostasis and complex behavior in animals. A dysregulated Hcrt/Orx system resulting from altered homeostasis (such as obesity) may contribute to the development of neurological and psychiatric diseases/conditions (eg, lowered arousal levels, weakened responses to salient stimuli) in animals as reported recently (49).
Figure 2.
Figure 2.
Local neuronal populations that interact with the Hcrt/Orx system. Hcrt/Orx cells and neighboring MCH-containing neurons receive reciprocal synaptic connections between them (59, 60). The Hcrt/Orx system is likely to be regulated indirectly by MCH and leptin through populations of MCHR1-expressing and LepRb-expressing neurons (61, 63, 64). A group of GABAergic neurons expressing dynorphin but not Hcrt/Orx receptors innervate Hcrt cells in the LHA, providing an additional inhibitory circuit onto these cells locally (65). Some other populations of GABAergic neurons expressing Hcrt/Orx receptors innervate MCH cells and may provide an inhibitory pathway onto these cells locally (66).
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